tbuckley/cabot-search huggingface dataset:
Quantifying the benefit of nonselective beta-blockers in the prevention of hepatic decompensation: A Bayesian reanalysis of the PREDESCI trial
Authors: Ian A. Rowe, Càndid Villanueva, Jessica E. Shearer, Ferran Torres, Agustín Albillos, Joan Genescà, Joan C. Garcia-Pagan, Dhiraj Tripathi, Peter C. Hayes, Jaume Bosch, Juan G. Abraldes
Journal: Hepatology (2023)

Beta-blockers have been studied for the prevention of variceal bleeding and, more recently, for the prevention of all-cause decompensation. Some uncertainties regarding the benefit of beta-blockers for the prevention of decompensation remain. Bayesian analyses enhance the interpretation of trials. The purpose of this study was to provide clinically meaningful estimates of both the probability and magnitude of the benefit of beta-blocker treatment across a range of patient types.We undertook a Bayesian reanalysis of PREDESCI incorporating 3 priors (moderate neutral, moderate optimistic, and weak pessimistic). The probability of clinical benefit was assessed considering the prevention of all-cause decompensation. Microsimulation analyses were done to determine the magnitude of the benefit. In the Bayesian analysis, the probability that beta-blockers reduce all-cause decompensation was >0.93 for all priors. The Bayesian posterior hazard ratios (HR) for decompensation ranged from 0.50 (optimistic prior, 95% credible interval 0.27-0.93) to 0.70 (neutral prior, 95% credible interval 0.44-1.12). Exploring the benefit of treatment using microsimulation highlights substantial treatment benefits. For the neutral prior derived posterior HR and a 5% annual incidence of decompensation, at 10 years, an average of 497 decompensation-free years per 1000 patients were gained with treatment. In contrast, at 10 years 1639 years per 1000 patients were gained from the optimistic prior derived posterior HR and a 10% incidence of decompensation.Beta-blocker treatment is associated with a high probability of clinical benefit. This likely translates to a substantial gain in decompensation-free life years at the population level.
<i>Ezh2</i> Knockout in B Cells Impairs Plasmablast Differentiation and Ameliorates Lupus‐like Disease in <scp>MRL</scp>/<i>lpr</i> Mice
Authors: Xiaoqing Zheng, Mikhail G. Dozmorov, Colleen E. Strohlein, Sheldon Bastacky, Amr H. Sawalha
Journal: Arthritis & Rheumatology (2023)

Objectives EZH2 regulates B cell development and differentiation. We previously demonstrated increased EZH2 expression in peripheral blood mononuclear cells from lupus patients. The goal of this study was to evaluate the role of EZH2 expression in B cells in the pathogenesis of lupus. Methods We generated an MRL/ lpr mouse with floxed Ezh2 , which was crossed with CD19‐Cre mice to examine the effect of B cell EZH2 deficiency in MRL/ lpr lupus‐prone mice. Differentiation of B cells was assessed using flow cytometry. Single‐cell RNA sequencing and single‐cell B cell receptor sequencing were performed. In vitro B cell culture with an X‐box binding protein 1 (XBP1) inhibitor was performed. EZH2 and XBP1 messenger RNA levels in CD19+ B cells isolated from lupus patients and healthy controls were analyzed. Results We show that Ezh2 deletion in B cells significantly decreased autoantibody production and improved glomerulonephritis. B cell development was altered in the bone marrow and spleen of EZH2‐deficient mice. Differentiation of germinal center B cells and plasmablasts was impaired. Single‐cell RNA sequencing showed that XBP1, a key transcription factor in B cell development, is down‐regulated in the absence of EZH2. Inhibiting XBP1 in vitro impairs plasmablast development similar to EZH2 deficiency in mice. Single‐cell B cell receptor RNA sequencing revealed defective immunoglobulin class‐switch recombination in EZH2‐deficient mice. In human lupus B cells, we observed a strong correlation between EZH2 and XBP1 messenger RNA expression levels. Conclusion EZH2 overexpression in B cells contributes to disease pathogenesis in lupus. image
Genetic mapping and molecular mechanism behind color variation in the Asian vine snake
Authors: Chen-Yang Tang, Xiaohu Zhang, Xiao Xu, Shijie Sun, Changjun Peng, Meng-Huan Song, Chaochao Yan, Huaqin Sun, Mingfeng Liu, Liang Xie, Shu-Jin Luo, Jia-Tang Li
Journal: Genome biology (2023)

Abstract Background Reptiles exhibit a wide variety of skin colors, which serve essential roles in survival and reproduction. However, the molecular basis of these conspicuous colors remains unresolved. Results We investigate color morph-enriched Asian vine snakes ( Ahaetulla prasina ), to explore the mechanism underpinning color variations. Transmission electron microscopy imaging and metabolomics analysis indicates that chromatophore morphology (mainly iridophores) is the main basis for differences in skin color. Additionally, we assemble a 1.77-Gb high-quality chromosome-anchored genome of the snake. Genome-wide association study and RNA sequencing reveal a conservative amino acid substitution (p.P20S) in SMARCE1 , which may be involved in the regulation of chromatophore development initiated from neural crest cells. SMARCE1 knockdown in zebrafish and immunofluorescence verify the interactions among SMARCE1 , iridophores, and tfec , which may determine color variations in the Asian vine snake. Conclusions This study reveals the genetic associations of color variation in Asian vine snakes, providing insights and important resources for a deeper understanding of the molecular and genetic mechanisms related to reptilian coloration.
Long-term Management Considerations for Retinal Artery Occlusion and Cardiovascular and Cerebrovascular Mortality
Authors: Sylvia E. Choi, Gregory Y. H. Lip, Azmil H. Abdul-Rahim
Journal: JAMA Network Open (2023)

Daniel Duck-Jin Hwang, MD, PhD; Kyung-Eun Lee, BA; Yuwon Kim, MSc; Myoung-Suk Kim, ME; Tyler Hyungtaek Rim, MD; Mina Kim, MS; Hasung Kim, MPH; Dae-Sung Kyoung, MBA; Ji In Park, MD, PhD
Life Expectancy Gaps Among Black and White Persons and Contributing Causes of Death in 3 Large US Cities, 2018-2019
Authors: Pamela T. Roesch, Nazia S. Saiyed, Emily Laflamme, Fernando G. De Maio, Maureen R. Benjamins
Journal: JAMA Network Open (2023)

US cities have substantial, but varying, levels of racial mortality inequities, a consequence of structural racism. As committed partners increasingly pledge to eliminate health inequities, local data are required to focus and unify efforts.To analyze the contributions of 26 cause-of-death categories to Black to White life expectancy gaps within 3 large US cities.In this cross-sectional study, data were extracted from the 2018 and 2019 National Vital Statistics System Multiple Cause of Death Restricted Use data files for deaths by race, ethnicity, sex, age, place of residence, and underlying and contributing causes of death in Baltimore, Maryland; Houston, Texas; and Los Angeles, California. Life expectancy at birth was calculated for non-Hispanic Black and non-Hispanic White populations overall and by sex using abridged life tables with 5-year age intervals. Data analysis was performed from February to May 2022.Using the Arriaga method, the proportion of the Black to White life expectancy gap was calculated overall and by sex for each city that was attributable to 26 cause-of-death categories defined using the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for underlying and contributing causes of death.A total of 66 321 death records from 2018 to 2019 were analyzed, with 29 057 individuals (44%) were identified as Black, 34 745 (52%) as male, and 46 128 (70%) as aged 65 years and older. Black to White life expectancy gaps were 7.60 years for Baltimore, 8.06 years for Houston, and 9.57 years for Los Angeles. Circulatory diseases, cancer, injuries, and diabetes and endocrine disorders were top contributors to the gaps, although the order and magnitude varied by city. The contribution of circulatory diseases was 11.3 percentage points higher in Los Angeles than in Baltimore (3.76 years [39.3%] vs 2.12 years [28.0%]). The contribution of injuries to Baltimore's racial gap (2.22 years [29.3%]) was twice as large as in Houston (1.11 years [13.8%]) and Los Angeles (1.36 years [14.2%]).By assessing the composition of Black to White life expectancy gaps for 3 large US cities and categorizing deaths at a more granular level than past studies, this study provides insight into the differing underpinnings of urban inequities. This type of local data can support local resource allocation that more effectively addresses racial inequities.
Mediation of Racial and Ethnic Inequities in the Diagnosis of Advanced-Stage Cervical Cancer by Insurance Status
Authors: Hunter K. Holt, Caryn E. Peterson, Shannon MacLaughlan David, Abdullah Abdelaziz, George F. Sawaya, Jenny S. Guadamuz, Gregory S. Calip
Journal: JAMA Network Open (2023)

Black and Hispanic or Latina women are more likely than White women to receive a diagnosis of and to die of cervical cancer. Health insurance coverage is associated with diagnosis at an earlier stage of cervical cancer.To evaluate the extent to which racial and ethnic differences in the diagnosis of advanced-stage cervical cancer are mediated by insurance status.This retrospective, cross-sectional population-based study used data from the Surveillance, Epidemiology, and End Results (SEER) program on an analytic cohort of 23 942 women aged 21 to 64 years who received a diagnosis of cervical cancer between January 1, 2007, and December 31, 2016. Statistical analysis was performed from February 24, 2022, to January 18, 2023.Health inusurance status (private or Medicare insurance vs Medicaid or uninsured).The primary outcome was a diagnosis of advanced-stage cervical cancer (regional or distant stage). Mediation analyses were performed to assess the proportion of observed racial and ethnic differences in the stage at diagnosis that were mediated by health insurance status.A total of 23 942 women (median age at diagnosis, 45 years [IQR, 37-54 years]; 12.9% were Black, 24.5% were Hispanic or Latina, and 52.9% were White) were included in the study. A total of 59.4% of the cohort had private or Medicare insurance. Compared with White women, patients of all other racial and ethnic groups had a lower proportion with a diagnosis of early-stage cervical cancer (localized) (American Indian or Alaska Native, 48.7%; Asian or Pacific Islander, 49.9%; Black, 41.7%; Hispanic or Latina, 51.6%; and White, 53.3%). A larger proportion of women with private or Medicare insurance compared with women with Medicaid or uninsured received a diagnosis of an early-stage cancer (57.8% [8082 of 13 964] vs 41.1% [3916 of 9528]). In models adjusting for age, year of diagnosis, histologic type, area-level socioeconomic status, and insurance status, Black women had higher odds of receiving a diagnosis of advanced-stage cervical cancer compared with White women (odds ratio, 1.18 [95% CI, 1.08-1.29]). Health insurance was associated with mediation of more than half (ranging from 51.3% [95% CI, 51.0%-51.6%] for Black women to 55.1% [95% CI, 53.9%-56.3%] for Hispanic or Latina women) the racial and ethnic inequities in the diagnosis of advanced-stage cervical cancer across all racial and ethnic minority groups compared with White women.This cross-sectional study of SEER data suggests that insurance status was a substantial mediator of racial and ethnic inequities in advanced-stage cervical cancer diagnoses. Expanding access to care and improving the quality of services rendered for uninsured patients and those covered by Medicaid may mitigate the known inequities in cervical cancer diagnosis and related outcomes.
Health Care Disparities in Pulmonary Fibrosis—Time to Move the Needle Forward
Authors: Yolanda N. Mageto
Journal: JAMA Network Open (2023)

Ayodeji Adegunsoye, MD, MS; Elizabeth Freiheit, PhD; Emily N. White, MA; Bhavika Kaul, MD; Chad A. Newton, MD, MSCS; Justin M. Oldham, MD, MS; Cathryn T. Lee, MD; Jonathan Chung, MD; Nicole Garcia, BA; Sahand Ghodrati, MD; Rekha Vij, MD; Renea Jablonski, MD; Kevin R. Flaherty, MD; Paul J. Wolters, MD; Christine Kim Garcia, MD, PhD; Mary E. Strek, MD
Incidence of Retinal Artery Occlusion and Related Mortality in Korea, 2005 to 2018
Authors: Daniel Duck-Jin Hwang, Kyung-Eun Lee, Yuwon Kim, Myoung-Suk Kim, Tyler Hyungtaek Rim, Mina Kim, Hasung Kim, Dae-Sung Kyoung, Ji In Park
Journal: JAMA Network Open (2023)

It remains unclear whether comorbidities in patients with retinal artery occlusion (RAO), a rare retinal vascular disorder, differ by subtype and whether mortality is higher.To examine the nationwide incidence of clinically diagnosed, nonarteritic RAO, causes of death, and mortality rate in patients with RAO compared with that in the general population in Korea.This retrospective, population-based cohort study examined National Health Insurance Service claims data from 2002 to 2018. The population of South Korea was 49 705 663, according to the 2015 census. Data were analyzed from February 9, 2021, to July 30, 2022.The nationwide incidence of any RAO, including central RAO (CRAO; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code, H34.1) and noncentral RAO (other RAO; ICD-10 code, H34.2) was estimated using National Health Insurance Service claims data from 2002 to 2018, with 2002 to 2004 as the washout period. Furthermore, the causes of death were evaluated and the standardized mortality ratio was estimated. The primary outcomes were the incidence of RAO per 100 000 person-years and the standardized mortality ratio (SMR).A total of 51 326 patients with RAO were identified (28 857 [56.2%] men; mean [SD] age at index date: 63.6 [14.1] years). The nationwide incidence of any RAO was 7.38 (95% CI, 7.32-7.44) per 100 000 person-years. The incidence rate of noncentral RAO was 5.12 (95% CI, 5.07-5.18), more than twice that of CRAO (2.25 [95% CI, 2.22-2.29]). Mortality was higher in patients with any RAO than in the general population (SMR, 7.33 [95% CI, 7.15-7.50]). The SMR for CRAO (9.95 [95% CI, 9.61-10.29]) and for noncentral RAO (5.97 [95% CI, 5.78-6.16]) showed a tendency toward a gradual decrease with increasing age. The top 3 causes of death in patients with RAO were diseases of the circulatory system (28.8%), neoplasms (25.1%), and diseases of the respiratory system (10.2%).This cohort study found that the incidence rate of noncentral RAO was higher than that of CRAO, whereas SMR was higher for CRAO than noncentral RAO. Patients with RAO show higher mortality than the general population, with circulatory system disease as the leading cause of death. These findings suggest that it is necessary to investigate the risk of cardiovascular or cerebrovascular disease in patients newly diagnosed with RAO.
Machine learning for accurate estimation of fetal gestational age based on ultrasound images
Authors: Lok Hin Lee, Elizabeth Bradburn, Rachel Craik, Mohammad Yaqub, Shane A. Norris, Leila Cheikh Ismail, Eric O. Ohuma, Fernando C. Barros, Ann Lambert, Maria Carvalho, Yasmin A. Jaffer, Michael Gravett, Manorama Purwar, Qingqing Wu, Enrico Bertino, Shama Munim, Aung Myat Min, Zulfiqar Bhutta, Jose Villar, Stephen H. Kennedy, J. Alison Noble, Aris T. Papageorghiou
Journal: npj Digital Medicine (2023)

Accurate estimation of gestational age is an essential component of good obstetric care and informs clinical decision-making throughout pregnancy. As the date of the last menstrual period is often unknown or uncertain, ultrasound measurement of fetal size is currently the best method for estimating gestational age. The calculation assumes an average fetal size at each gestational age. The method is accurate in the first trimester, but less so in the second and third trimesters as growth deviates from the average and variation in fetal size increases. Consequently, fetal ultrasound late in pregnancy has a wide margin of error of at least ±2 weeks' gestation. Here, we utilise state-of-the-art machine learning methods to estimate gestational age using only image analysis of standard ultrasound planes, without any measurement information. The machine learning model is based on ultrasound images from two independent datasets: one for training and internal validation, and another for external validation. During validation, the model was blinded to the ground truth of gestational age (based on a reliable last menstrual period date and confirmatory first-trimester fetal crown rump length). We show that this approach compensates for increases in size variation and is even accurate in cases of intrauterine growth restriction. Our best machine-learning based model estimates gestational age with a mean absolute error of 3.0 (95% CI, 2.9-3.2) and 4.3 (95% CI, 4.1-4.5) days in the second and third trimesters, respectively, which outperforms current ultrasound-based clinical biometry at these gestational ages. Our method for dating the pregnancy in the second and third trimesters is, therefore, more accurate than published methods.
A liposomal vaccine promotes strong adaptive immune responses via dendritic cell activation in draining lymph nodes
Authors: Maria Agallou, Maritsa Margaroni, Evgenia Tsanaktsidou, Fotis Badounas, Olga Kammona, Costas Kiparissides, Evdokia Karagouni
Journal: Journal of Controlled Release (2023)

Subunit proteins provide a safe source of antigens for vaccine development especially for intracellular infections which require the induction of strong cellular immune responses. However, those antigens are often limited by their low immunogenicity. In order to achieve effective immune responses, they should be encapsulated into a stable antigen delivery system combined with an appropriate adjuvant. As such cationic liposomes provide an efficient platform for antigen delivery. In the present study, we describe a liposomal vaccine platform for co-delivery of antigens and adjuvants able to elicit strong antigen-specific adaptive immune responses. Liposomes are composed of the cationic lipid dimethyl dioctadecylammonium bromide (DDAB), cholesterol (CHOL) and oleic acid (OA). Physicochemical characterization of the formulations showed that their size was in the range of ∼250 nm with a positive zeta potential which was affected in some cases by the enviromental pH facilitating endosomal escape of potential vaccine cargo. In vitro, liposomes were effectively taken up by bone marrow dendritic cells (BMDCs) and when encapsulated IMQ they promoted BMDCs maturation and activation. Upon in vivo intramuscular administration, liposomes' active drainage to lymph nodes was mediated by DCs, B cells and macrophages. Thus, mice immunization with liposomes having encapsulated LiChimera, a previously characterized anti-leishmanial antigen, and IMQ elicited infiltration of CD11blow DCs populations in draining LNs followed by increased antigen-specific IgG, IgG2a and IgG1 levels production as well as indcution of antigen-specific CD4+ and CD8+ T cells. Collectively, the present work provides a proof-of-concept that cationic liposomes composed of DDAB, CHOL and OA adjuvanted with IMQ provide an efficient delivery platform for protein antigens able to induce strong adaptive immune responses via DCs targeting and induction of maturation.
Glofitamab therapy for diffuse large B cell lymphoma: latest updates from the 2022 ASH Annual Meeting
Authors: Chaoyu Wang, Yao Liu
Journal: Journal of Hematology & Oncology (2023)

Over one-third of B cell lymphomas are not effectively treated by R-CHOP chemotherapy. When lymphoma relapses or is refractory, the prognosis becomes very poor. Due to this fact, there is an urgent and clear requirement for a more effective, novel treatment option. Glofitamab is a CD20xCD3 T-cell-engaging, bispecific antibody capable of recruiting T cells to tumor cells. We have summarized several of the latest reports on glofitamab use in B cell lymphoma therapy from the 2022 ASH Annual Meeting (ASH2022).
Microbiota-directed biotherapeutics: considerations for quality and functional assessment
Authors: Emily Ef Fekete, Daniel Figeys, Xu Zhang
Journal: Gut Microbes (2023)

Mounting evidence points to causative or correlative roles of gut microbiome in the development of a myriad of diseases ranging from gastrointestinal diseases, metabolic diseases to neurological disorders and cancers. Consequently, efforts have been made to develop and apply therapeutics targeting the human microbiome, in particular the gut microbiota, for treating diseases and maintaining wellness. Here we summarize the current development of gut microbiota-directed therapeutics with a focus on novel biotherapeutics, elaborate the need of advanced -omics approaches for evaluating the microbiota-type biotherapeutics, and discuss the clinical and regulatory challenges. We also discuss the development and potential application of ex vivo microbiome assays and in vitro intestinal cellular models in this context. Altogether, this review aims to provide a broad view of promises and challenges of the emerging field of microbiome-directed human healthcare.
Estimated Effectiveness of Prior SARS-CoV-2 BA.1 or BA.2 Infection and Booster Vaccination Against Omicron BA.5 Subvariant Infection
Authors: Eun Jung Jang, Young June Choe, Ryu Kyung Kim, Sangwon Lee, Seon Kyeong Park, Young-Joon Park
Journal: JAMA Network Open (2023)

This case-control study estimates the effectiveness of prior SARS-CoV-2 BA.1 or BA.2 infection and booster vaccination against Omicron BA.5 subvariant infection.
HBV with precore and basal core promoter mutations exhibits a high replication phenotype and causes ER stress-mediated cell death in humanized liver chimeric mice
Authors: Takuro Uchida, Michio Imamura, C. Nelson Hayes, Yosuke Suehiro, Yuji Teraoka, Kazuki Ohya, Hiroshi Aikata, Hiromi Abe-Chayama, Yuji Ishida, Chise Tateno, Yuichi Hara, Keisuke Hino, Toru Okamoto, Yoshiharu Matsuura, Hideki Aizaki, Kenjiro Wake, Michinori Kohara, T. Jake Liang, Shiro Oka, Kazuaki Chayama
Journal: Hepatology (2023)

Background and Aims: Mutations within the precore (PC) and basal core promoter (BCP) regions of the HBV genome are associated with fulminant hepatitis and HBV reactivation. These mutations may enhance viral replication, but little is known about whether they directly induce damage to the liver. We investigated mechanisms of direct cytopathic effects induced by the infection with PC/BCP mutants in the absence of immune response in vitro and in vivo . Approach and Results: Mice with humanized livers and hepatocytes derived from humanized mice were infected with either wild-type or mutant-type PC/BCP HBV, and the HBV replication and human hepatocyte damage were evaluated. HBV proliferated vigorously in mice with PC/BCP-mutant infection, and the severe loss of human hepatocytes with a slight human ALT elevation subsequently occurred only in PC/BCP mutant mice. In PC/BCP mutant infection, the accumulation of HBsAg in humanized livers colocalized with the endoplasmic reticulum, leading to apoptosis through unfolded protein response in HBV-infected hepatocytes. RNA-sequencing revealed the molecular characteristics of the phenotype of PC/BCP mutant infection in a humanized mouse model. Reduced ALT elevation and higher HBV DNA levels in this model are consistent with characteristics of HBV reactivation, indicating that the hepatocyte damage in this model might mimic HBV reactivation followed by hepatocyte damage under immunosuppressive conditions. Conclusion: PC and BCP mutations were associated with enhanced viral replication and cell death induced by ER stress using HBV infection models. These mutations might be associated with liver damage in patients with fulminant hepatitis or HBV reactivation.